Diacerein-containing medicines for oral administration - referral

Current status

European Commission final decision

Overview

Restrictions to the use of diacerein-containing medicines

Restrictions intended to limit risks of severe diarrhoea and effects on the liver

On 19 March 2014, the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh)¹ endorsed recommendations to restrict the use of diacerein-containing medicines in order to manage the risks of severe diarrhoea and effects on the liver.

Due to the risks associated with severe diarrhoea, diacerein is no longer recommended in patients aged 65 years and above. It is also advised that patients start treatment on half the normal dose (i.e. 50 mg daily instead of 100 mg) and should stop taking diacerein if diarrhoea occurs.

In addition, diacerein-containing medicines must now not be used in any patient with liver disease or a history of liver disease, and doctors should be monitoring their patients for early signs of liver problems.

Doctors should also note that, based on available data, the use of diacerein is to be limited to treating symptoms of osteoarthritis affecting the hip or knee. Treatment should only be started by doctors experienced in treating osteoarthritis.

These recommendations are based on the review of the benefits and risks of diacerein conducted by the EMA's Pharmacovigilance and Risk Assessment Committee (PRAC) and follow concerns raised by the French medicines agency (ANSM) about diacerein's gastro-intestinal and liver effects. The CMDh endorsed the PRAC's final recommendations to address these concerns and ensure that diacerein's benefits continue to outweigh its known risks.

As the CMDh position on diacerein was adopted by majority vote, it was sent to the European Commission which endorsed it and issued a final legally binding decision valid throughout the European Union (EU) on 4 September 2014.

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¹The CMDh is a medicines regulatory body representing the European Union (EU) Member States.

Information to patients

Diacerein is a medicine used to treat joint diseases such as osteoarthritis (swelling and pain in the joints). Following an EU-wide review of diacerein, its use has been restricted in order to minimise the risks of severe diarrhoea and liver problems.

Patients are advised of the following:

• Diacerein should only be used for treating symptoms of osteoarthritis affecting the hip or knee.
• If you have diarrhoea while taking diacerein, stop taking your medicine and contact your doctor to discuss which other treatments you can take.
• If you are taking diacerein and you are 65 years or above, contact your doctor to discuss your treatment.
• You should not take diacerein if you have or have had liver problems. Your doctor will monitor your liver function on a regular basis and advise about the symptoms of liver problems (such as pruritus (itching) and jaundice). Contact your doctor if you have symptoms of liver problems.
• If you have any questions about your treatment, please contact your doctor or pharmacist.

Information to healthcare professionals

• Due to the risks associated with severe diarrhoea:
  • it is advisable to start treatment with half the normal dose (i.e. 50 mg per day) for the first 2 to 4 weeks, after which the recommended dose is 50 mg twice a day.
  • treatment should be stopped if diarrhoea occurs.
  • diacerein is not recommended in patients aged 65 years or above.
• Diacerein must not be used in any patient with liver disease or a history of liver disease. Doctors should be monitoring their patients for early signs of liver problems and advising them how to recognise early symptoms.
• Diacerein should only be used to treat symptoms of osteoarthritis of the hip or knee and it is not recommended for rapidly progressive hip osteoarthritis.
• Treatment should only be started by doctors experienced in treating osteoarthritis.

The recommendations are based on a review of available data on the efficacy and safety of diacerein. Efficacy in the symptomatic treatment of osteoarthritis of the hip or knee was shown in published studies where diacerein was superior to placebo in relieving pain^1-5. The first beneficial effects of diacerein in these studies were seen after 2 to 4 weeks of continuous use.

With regard to safety, loose stools or diarrhoea were the most frequently reported adverse events in clinical studies with diacerein at a dose of 100 mg per day. The proportion of patients with diarrhoea in clinical trials ranged from 0% to 54.4%. In the majority of cases diacerein-induced diarrhoea started in the first weeks of treatment.

Elevated serum liver enzymes and cases of symptomatic acute hepatic injury have been reported in the post-marketing phase with diacerein. In clinical studies, around 0.5% of patients on diacerein had some kind of liver reaction, with most cases being mild, reversible increases in serum transaminases. The proportion of patients who develop drug-induced liver injury following treatment with diacerein is estimated to be 0.03%.

References

1. Lequesne M, Berdah L, Gérentes I. Efficacy and Safety of Diacerein for the treatment of Knee and Hip Osteoarthritis [Efficacité et tolérance de la diacerhéine dans le traitment de la gonarthrose et de la coxarthrose]. La Revue du Praticien 1998;48:S31-S35
2. Pavelka K, Trc T, Karpas K, Vítek P, Sedlacková M, Vlasáková V, Böhmová J, Rovenský J. The Efficacy and Safety of Diacerein in the Treatment of Painful Osteoarthritis of the Knee. Arthritis & Rheumatism 2007;56:4055-4064.
3. Singh K, Sharma R, Rai J. Diacerein as adjuvant to diclofenac sodium in osteoarthritis knee. International Journal of Rheumatic Diseases 2012;15(1):69-77.
4. Pelletier JP, Yaron M, Haraoui B, Cohen P, Nahir M A, Choquette D, et al. Efficacy and Safety of Diacerein in Osteoarthritis of the Knee. Arthritis and Rheumatism 2000;43(10):2339-2348.
5. Nguyen M, Dougados M, Berdah L, Amor B. Diacerhein in the treatment of osteoarthritis of the hip. Arthritis Rheum. 1994 Apr;37(4):529-36.

More about the medicine

Diacerein is a slow-acting medicine of the class 'anthraquinones' used to treat joint diseases such as osteoarthritis (swelling and pain in the joints).It works by blocking the actions of interleukin?1 beta, a protein involved in the inflammation and destruction of cartilage that play a role in the development of symptoms of degenerative joint diseases such as osteoarthritis.

Diacerein-containing medicines are taken by mouth and are currently authorised in the following EU Member States: Austria, Czech Republic, France, Greece, Italy, Portugal, Slovakia and Spain.

More about the procedure

The review of diacerein-containing medicines was initiated on 29 November 2012 at the request of the French medicines agency under Article 31 of Directive 2001/83/EC.

The review of diacerein was conducted by the Pharmacovigilance Risk Assessment Committee (PRAC). In November 2013, the PRAC initially recommended the suspension of the marketing authorisations for diacerein-containing medicines. However, following re-examination, the PRAC considered additional proposals to manage diacerein's risks and was satisfied that with new restrictions diacerein's benefits would outweigh its risks.

The PRAC's final recommendations were sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which endorsed the recommendations and adopted a position by majority vote.

The CMDh position was sent to the European Commission which endorsed it and issued an EU-wide legally binding decision on 4 September 2014.

Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines

Reference Number: EMA/544268/2014

Key facts

About this medicine

• Approved name:
  Diacerein-containing medicines for oral administration
• International non-proprietary name (INN) or common name:
  diacerein
• Associated names:
  Zondar
• Class:
  -

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1349
• Type:
  Article 31 referrals

  This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

• Authorisation model:
  Nationally authorised product(s)
• Decision making model:
  PRAC-CMDh

Key dates and outcomes

• Procedure start date:
  29/11/2012
• PRAC recommendation date:
  06/03/2014
• CMDh position date:
  23/07/2014
• EC decision date:
  04/09/2014
• Outcome:
  Variation

All documents

Procedure started

Diacerein Article-31 referral - Annex I

Reference Number: EMA/764460/2012

Diacerein Article-31 referral - Timetable for the procedure

Reference Number: EMA/PRAC/747322/2012

Diacerein Article-31 referral - PRAC list of questions

Reference Number: EMA/PRAC/759123/2012 Rev.1

Diacerein Article-31 referral - Review started

Reference Number: EMA/762522/2012

Diacerein Article-31 referral - Notification

Recommendation provided by Pharmacovigilance Risk Assessment Committee

PRAC re-examines diacerein and recommends that it remain available with restrictions

Reference Number: EMA/133894/2014

PRAC recommends suspension of diacerein-containing medicines

Reference Number: EMA/679264/2013/rev. 2

Position provided by CMDh

Diacerein Article-31 referral - Annex III

CMDh endorses recommendations to restrict the use of diacerein-containing medicines

Reference Number: EMA/162540/2014

European Commission final decision

Diacerein Article-31 referral - Annex III

Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines

Reference Number: EMA/544268/2014

Diacerein Article-31 referral - Annex II

Diacerein Article-31 referral - CMDh divergent position

Diacerein Article-31 referral - PRAC assessment report

Diacerein Article-31 referral - Annex I

Diacerein Article-31 referral - Annex IV

Diacerein Article-31 referral - Restrictions to the use of diacerein-containing medicines

Reference Number: EMA/544268/2014

Description of documents published

Please note that some of the listed documents apply only to certain procedures.

• Overview - lay-language summary of the stage of the procedure
• Notification – a letter from a Member State, the European Commission or the marketing authorisation holder requesting the initiation of the procedure
• Scientific background – further background information from the triggering Member State on the issues leading to the initiation of the procedure (if applicable)
• List of questions – questions agreed by the Committee requesting further information from the marketing authorisation holder(s) / applicant(s) to evaluate the issues identified
• Timetable for the procedure – agreed timeframe to respond to the list of questions, to assess the issues and to adopt a conclusion
• List of medicines concerned by the procedure – medicine(s) / active substance(s) concerned, and marketing authorisation holder(s) / applicant(s)
• List of questions to be addressed by the stakeholders – call for data to be submitted by stakeholders (e.g. healthcare professionals, patient organisations, individual patients) (if applicable)
• Stakeholder submission form – form to be used by stakeholders to submit data (if applicable)
• Scientific conclusions – scientific conclusions of the PRAC and/or CHMP and/or CMDh
• Assessment report – PRAC or CHMP assessment and conclusions on the issues investigated, including divergent positions (if applicable)
• Divergent positions – divergent positions of the CHMP or CMDh members for pharmacovigilance procedures (if applicable)
• Changes to the summary of product characteristics, labelling and package leaflet (amended sections or fully revised version) (if applicable)
• Condition(s) to the marketing authorisation(s) – condition(s) for the safe and effective use of the medicine(s) (if applicable)
• Condition for lifting the suspension – condition to be fulfilled for the suspension of the marketing authorisation(s) to be lifted (if applicable)
• Timetable for implementation of CMDh position – agreed timeframe to submit and finalise the variation(s) implementing the outcome of the procedure (if applicable)

Note that older documents may have different titles.